The immune system functions to protect individuals from infective agents, e.g., bacteria, multi-cellular organisms, and viruses, as well as from cancers. This system includes several types of lymphoid and myeloid cells such as monocytes, macrophages, dendritic cells (DCs), eosinophils, T cells (including helper T cells, Th cells), B cells, and neutrophils. These lymphoid and myeloid cells often produce signaling proteins known as cytokines. The immune response includes inflammation, i.e., the accumulation of immune cells systemically or in a particular location of the body. In response to an infective agent or foreign substance, immune cells secrete cytokines which, in turn, modulate immune cell proliferation, development, differentiation, or migration.
Although the immune system has a beneficial role in protection from infections and malignancies, inappropriate and/or uncontrolled immune responses can lead to immunopathology. Immune response can produce pathological consequences, e.g., when it involves excessive inflammation, as in the autoimmune disorders. See, e.g., Abbas et al. (eds.) (2000) Cellular and Molecular Immunology, W.B. Saunders Co., Philadelphia, Pa.; Oppenheim and Feldmann (eds.) (2001) Cytokine Reference, Academic Press, San Diego, Calif.; von Andrian and Mackay (2000) New Engl. J. Med. 343:1020-1034; Davidson and Diamond (2001) New Engl. J. Med. 345:340-350. Inappropriate immune responses include allergic responses to an innocuous environmental antigens, such an a Th2-biased immune response. Immunopathology can also result from cell-based immune responses that occur in the absence of infection, or persist after resolution of an initial triggering infection. Chronic inflammation can also result from inappropriate immune response to self-antigens, as in the case of autoimmune disease, or other persistent antigens (such as commensal flora). Autoimmune inflammatory disorders include inflammation of the joints, central nervous system (CNS), skin, gut and other organs. Such diseases include rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis (Pso), and inflammatory bowel disorder (IBD), including Crohn's disease (CD) and ulcerative colitis (UC).
RA is a progressive, systemic disease characterized by inflammation of the synovial joints affecting about 0.5% of the world's population. Emery (2006) BMJ 332:152-155. Joint inflammation can lead to deformity, pain, stiffness and swelling, and ultimately to irreversible deterioration of the joint. Affected joints include knees, elbows, neck and joints of the hands and feet. Conventional treatment involves use of NSAIDs to alleviate symptoms, followed by administration of disease modifying antirheumatic drugs (DMARDs) such as gold, penicillamine, sulfasalazine and methotrexate. Recent advances include treatment with TNF-α inhibitors, including monoclonal antibodies, such as infliximab (REMICADE®), adalimumab (HUMIRA®) and golimumab (SIMPONI®), and receptor fusion proteins, such as etanercept (ENBREL®), and other TNF-α antagonists such as certolizumab pegol (CIMZIA®), golimumab, and natalizumab (TYSABRI®). Treatment with these TNF-α inhibitors dramatically reduces structural damage from the disease.
MS is thought to be an autoimmune disease of the central nervous system (CNS) involving loss of myelin from nerve fibers, resulting in plaques or lesions. The most common form is relapsing/remitting MS in which well defined symptomatic flare-ups occur, followed by periods of partial or complete remission. Conventional treatment options include interferon-β-1a and -1b, mitoxantrone, the tetrapeptide glatiramer acetate, therapeutic alpha-4-integrin-specific antibodies (natalizumab), or small molecule antagonists of alpha-4-integrin (e.g. those disclosed at WO 2003/084984).
The skin serves as an important boundary between the internal milieu and the environment, preventing contact with potentially harmful antigens. In the case of antigen/pathogen penetration, an inflammatory response is induced to eliminate the antigen. This response leads to a dermal infiltrate that consists predominantly of T cells, polymorphonuclear cells, and macrophages (see, e.g., Williams and Kupper (1996) Life Sci., 58:1485-1507.) Normally, this inflammatory response, triggered by the pathogen, is under tight control and will be halted upon elimination of the pathogen.
Psoriasis is characterized by T cell mediated hyperproliferation of keratinocytes coupled with an inflammatory infiltrate. The disease has certain distinct overlapping clinical phenotypes including chronic plaque lesions, skin eruptions, and pustular lesions (see, e.g., Gudjonsson et al. (2004) Clin Exp. Immunol. 135:1-8). Approximately 10% of psoriasis patients develop arthritis. The disease has a strong but complex genetic predisposition, with 60% concordance in monozygotic twins. The typical psoriatic lesion is a well defined erythematosus plaque covered by thick, silvery scales. The inflammation and hyperproliferation of psoriatic tissue is associated with a different histological, antigenic, and cytokine profile than normal skin. Among the cytokines associated with psoriasis are: TNFα, IL-19, IL-18, IL-15, IL-12, IL-7, IFNγ, IL-17A and IL-23 (see Gudjonsson et al., supra).
Crohn's disease and ulcerative colitis (collectively Inflammatory Bowel Disease, or IBD) are chronic, inflammatory diseases of the gastrointestinal tract. Both disorders are characterized by abdominal pain, diarrhea (often bloody), a variable group of “extra-intestinal” manifestations (such as arthritis, uveitis, skin changes, etc.) and the accumulation of inflammatory cells within the small intestine and colon. Additional symptoms, aspects, manifestations, or signs of IBD include malabsorption of food, altered bowel motility, infection, fever, rectal bleeding, weight loss, signs of malnutrition, perianal disease, abdominal mass, and growth failure, as well as intestinal complications such as stricture, fistulas, toxic megacolon, perforation, and cancer, and including endoscopic findings, such as, friability, aphthous and linear ulcers, cobblestone appearance, pseudopolyps, and rectal involvement and, in addition, anti-yeast antibodies. See, e.g., Podolsky (2002) New Engl. J. Med. 347:417-429; Hanauer (1996) New Engl. J. Med. 334:841-848; Horwitz and Fisher (2001) New Engl. J. Med. 344:1846-1850.
IBD affects both children and adults, and has a bimodal age distribution (one peak around 20, and a second around 40). IBD affects over 600,000 Americans. IBD is a chronic, lifelong disease, and is often grouped with “autoimmune” disorders (e.g. rheumatoid arthritis, type I diabetes mellitus, multiple sclerosis, etc.). IBD is found almost exclusively in the industrialized world. An estimated one million Americans are believed to have IBD, half of which have CD and half of which have UC. Hanauer (2006) Inflamm. Bowel Dis. 12:S3. There is an unexplained trend towards increasing incidence of IBD, particularly Crohn's Disease, in the U.S. and Europe.
Treatment of IBD is varied. First line therapy typically includes salicylate derivatives (e.g. 5-ASA) given orally or rectally. Corticosteroids (e.g. prednisone) are also used, despite the untoward side-effects, as well as immunomodulators such as sulfasalazine, azathioprine, methotrexate and 6-mercaptopurine, or an antibiotic (e.g. metronidazole) for Crohn's disease. Therapeutic monoclonal antibody treatments include infliximab (REMICADE®), a chimeric antibody directed to TNF-α, and other TNF-α antagonists such as adalimumab ( HUMIRA®), certolizumab pegol (CIMZIA®), golimumab, and natalizumab ( TYSABRI®).
The need exists for therapeutic agents and methods for treatment of immune disorders, such as allergic responses, autoimmune and inflammatory disorders, such as those that occur in the CNS, skin, joints and gut.